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Browsing Doctoral Theses by Supervisor "Debnath, Ananya"
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Item Dynamical Heterogeneity of Interface Water upon Membrane Phase Transitions(Indian Institute of Technology Jodhpur, 2023-01) Debnath, AnanyaLipid bilayers are essential components of cell membranes because they serve as semi-permeable barriers between the extracellular and intracellular environments. Fluid (Lα ), ripple (Pβ ), and gel (Lβ ) are the three primary phases of lipid membranes. The functionality of the cell membrane is active at its fluid phase and at a full hydration level. A co-existence in the gel and the fluid phases in membranes results in the creation of grain boundary defects and helps in a drug release. Water molecules near membranes regulate various properties of the cell such as transport, raft formation, molecular recognition, signal transduction and so on. Such water have different characteristics than bulk water (BW). Thus understanding the role of water on the membrane phase transitions is crucial to control the function of membrane under physiological and low temperature conditions. Although water dynamics and thermodynamics around membranes have been found to be correlated with the phase transition, the underlying mechanism of the correlation is not explored and not characterized. The current thesis provides evidences of emergence of dynamical heterogeneity in interface water (IW) near membranes at three phases using all-atom molecular dynamics simulations. The correlation between the structure and dynamics of the IW and membranes are quantified across fluid to ripple to gel phase transitions. To understand whether the regional coupling of lipid and water dynamics is significant enough to capture any perturbation in fluid membrane, we identify IW near a fluid membrane composed of 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) lipids. IW residing within a distance of ±0.35 nm of the locations of the most probable density of CO/PO/Glyc. heads of DMPC molecules are referred to as IW-COd/POd/Glycd . All IW molecules manifest signatures of dynamical heterogeneity at room temperature due to regional confinement and exhibit multiple structural relaxation time-scales. Both fast and slow relaxation time scales of the IWd are correlated to the respective time scales of the closest lipid moieties. These analyses imply that the spatially resolved interface water dynamics can act as a sensitive reflector of regional membrane dynamics occurring at sub ps to hundreds of ps time scales and thus will be able to capture any alterations in membrane structure and function in future. Since membranes are active at a fully hydrated state and the cells die upon dehydration, understanding biological cell membranes under anhydrous conditions is of tremendous importance. We find that the bilayer undergoes from a disordered state to a ordered state upon dehydration with a drastic slow-down in the relaxation times of the IW originated from dynamical heterogeneity. The diffusion constants and the structural relaxation times of the IW obey the Stokes-Einstein (SE) relation for the bilayer fluid phase which changes to a fractional SE-like relation at the onset of bilayer ordering. Thus, our analysis provides the mechanistic insights of dehydration induced bilayer ordering. To understand the structural changes of the IW due to bilayer phase transitions, we perform a ∼ 11.55μs long all-atom molecular dynamics simulation at the gel, ripple and the fluid phases of the bilayers. The first and second peak heights of the radial distribution functions (RDF) of the BW increase monotonically with a decrease in temperature, signifying the presence of enhanced tetrahedrality at the lowest temperature which is below the homogeneous ice nucleation temperature accessing the ”no man’s land”. Similar behaviour is observed for the IW near fluid and gel phases but not for the ripple phase, probably due to the curvature induced in the ripple phase. Changes in locations of the first and the second hydration shells show two crossovers near fluid to ripple and ripple to gel phase transitions. The angular distribution functions of the IW near the fluid bilayers exhibit peaks corresponding to a distorted tetrahedral arrangement similar to the high-density liquid (HDL) phase due to the presence of interstitials. This changes to tetrahedral arrangement for the IW near the gel bilayer, indicating the presence of low-density liquid (LDL) like phases. As temperature reduces, membrane phase transitions are associated with a drastic slow down in structural relaxation times of the interface water (IW) and the lipids originated from dynamical heterogeneity. Diffusion constants of the IW undergo dynamic crossovers at both fluid-to-ripple-to-gel phase transitions with the highest activation energy near the gel phase leading to a stronger correlation of the IW dynamics with the gel membrane due to larger number of hydrogen bonds. Similar to the BW, Stoke Einstein (SE) relations are conserved for the IW near all three phases of membranes for the time scales derived from the diffusion exponents and the non-Gaussian parameters, indicating that these time scales are coupled with the diffusion even at lower temperatures. However, the SE relationship breaks for the time scales calculated from the self intermediate scattering functions. The behavioural differences in these different time scales upon supercooling are found to be universal irrespective of the nature of the water and other glass forming liquids. The spatial correlation length scale of the heterogeneous local dynamics of the IW are captured from the data collapse of block size dependent Binder cumulant which is a scaling function of only the underlying correlation length. The dynamical length of the IW is found to have inverse power law dependence on temperature for the fluid phase. The dependence becomes very weak for the gel phase unlike glass forming liquids. Interestingly, the dynamical length scale of the IW near the ripple phase is temperature independent and thus, can capture to the domain size of the ripple signifying a possibility of probing the heterogeneity length scale of a bio-membrane from its curvature induced domain size. The length scale is monotonically dependent on the first peak of the radial distribution function of the IW near all phases this suggests that the heterogeneity length scale is structure dominated. Our analyses, for the first time, estimate the coupling between the spatio-temporal scales of the IW and membranes across phase transitions. The structural relaxations of the IW follow an activated dynamical scaling with the heterogeneity length scale only for the gel phase which is similar to that predicted from the random first order transition theory. However, the drastic growths in the heterogeneity length scale across phase transitions are not accompanied by similar growth in the heterogeneity time scales. This is because, the growing structural relaxation time scales of the IW are dominated by the supercooling whereas the growing length scales are dictated by the membrane phase transitions. In summary, the thesis sheds light on how the structure and dynamics of lipids and IW are correlated across a wide range of temperature and hydration numbers relevant for physiological and extreme conditions. Our findings suggest that hydration water dynamics can sensitively reflect localized membrane movements and thus can be an alternate tool to probe any perturbations in membranes. These can help to understand drug delivery mechanisms and mimic cryo preservation procedures for use in biomedical applications in the future.Item Self-assembly of Surfactants and Bio-inspired Soft Materials for Desired Macroaggregates using Multiscale Simulations.(Indian Institute of Technology Jodhpur, 2021-01) Debnath, AnanyaSurfactants and soft materials neither belong to the class of simple liquids nor can be defined as crystalline solids. Due to the similarities in their length scales, random motions, spontaneous self-assembly formation and structural alterations by temperature and mechanical stress, these materials are worthy to be studied under ”soft matter”. These materials are broadly applicable as cosmetic products, hydrogels, drug-delivery, bio-mimetic and bio-inspired materials and so on. In order to target desirable functionalities of supra-structures comprised of these molecules, it is important to gain molecular level insights on their physical interactions and thermodynamical properties. Thus, the present thesis focuses on understanding the self-assembly of surfactants and π-conjugated peptide derivatives into macro-aggregates of different topologies using multiscale simulations.Surfactants are a class of amphiphilic molecules which can self-assemble into micelles, bilayers, vesicles etc. depending on parameters such as temperature, pH, packing fraction and so on. Identifying the parameters which control a topology of a molecular assembly is the key to obtain materials with a targeted functionality as functionalities of materials are often found to be dependent on their topologies. In this work, we first explore the influence of water content on the self-assembly of a cationic surfactant, behenyltrimethylammonium chloride (BTMAC) and a co-surfactant, stearyl alcohol (SA) at a fixed ratio of 2:1 and constant temperature using all-atom (AA) molecular dynamics (MD) simulations. We construct a water directed phase diagram where an interdigitated lamellar phase and spherical micelles are self-assembled at low and high water contents respectively. Next, to identify the controlling factors for shape transformations in micelles and to achieve the relevant length and time scales, we derive a coarse-grained (CG) model using the all atom (AA) model. The bonded potentials for CG BTMAC and SA are obtained by the Boltzmann inversion of the respective AA bonded distributions, whereas the non-bonded terms are obtained from the MARTINI force-field. We find that a systematic parameterization of the non-bonded terms in MARTINI leads to similar micellar size distributions as obtained from the AA simulations. The CG simulations demonstrate that the interplay between the head-group size and hydrophilicity is crucial in obtaining the desired micelle size. Next, we try to understand the effect of asymmetry on lateral organizations of bilayers at a constant ratio of BTMAC to SA at a constant temperature by employing multiscale simulations. The surfactants self-assemble into bilayers at gel or ripple phases with variable compositional asymmetry. The rippling in bilayers is attributed to the trans-leaflet inhomogeneous populations of disordered molecules with higher per chain configurational entropy and tilt. Our results indicate that the trans-leaflet compositional asymmetry can transform a bilayer from a square phase or a one dimensional ripple phase to a gel phase at both AA and CG scales. A coupling between the order parameters and per chain configurational entropy of the surfactant chains indicates that the order parameter of a bilayer can serve as a reflector of per chain configurational entropy, which is otherwise inaccessible to the experiments. The relation between entropy and bilayer properties can be utilized to construct an entropy-meter, similar to proteins. Due to the similarities of the surfactants to lipid molecules, the present analysis can be applied to understand the domain assisted transport and signalling at low temperatures in naturally existing complex biological membranes.π-conjugated peptide derivatives belong to a class of bio-inspired soft materials which have vast applications in nanoscience, material science and medical engineering due to the unique combination of π-conjugation and peptide chemistry. Experimental findings demonstrate vthat peptide-perylenediimide conjugate (P-1) molecules self-assemble into right-handed helical supra-structures with high semi-conducting properties which transform into nano-rings based upon solvent concentrations. To identify the preferential geometry of a peptide-perylenediimide conjugate (P-1) molecule as a building block of a specific supra-structure, we calculate the binding energies of dimers of P-1 by employing subsequent electronic structure calculations and AA-MD simulations in water. Stronger binding energies are found for the dimer with left-handed helicity compared to the right-handed one due to more π − π interactions due to less number of inter-molecular hydrogen bonding between the P-1 molecules. Lower number of inter-molecular hydrogen bonding in the left-handed dimer permits the aromatic side rings to orient themselves for a better π-π interactions unlike the right-handed dimer. Thus left-handed nano-rings are identified as the thermodynamically preferred arrangement over the kinetically controlled right-handed helix as in the experiment. Another small amphiphilic peptide-conjugate molecule, PyKC forms a hydrogel with prolonged insolubility in water although amphiphilic moieties are present in the molecule. To gain a molecular level understanding of the unique behavior of the hydrogel, we use electronic structure calculations followed by AA-MD simulations in water. PyKC dimers self-assemble into a network like structure forming PyKC layers which have a distinct PyKC-water interface. The stability of the hydrogel is attributed to intra-molecular hydrogen bonds within the PyKC and both T-type and H-type π − π interactions of the pyrene rings. The pyrene rings being exposed towards the bulk water act as a hydrophobic shield for the amphiphilic moities of PyKC which are buried inside the hydrogel core. This prevents the amphiphilic moities from the water molecules outside the hydrogel attributing towards the lower water solubility of the hydrogel. The shielded amphiphilic groups bring few water molecules along with them which remain trapped inside the hydrogel core due to strong inter-molecular hydrogen bondings among themselves and the amphiphilic moities of PyKC. The unique compartmentalization feature of this hydrogel can open a pathway to solve bigger challenges in biomedical applications.Thus, the thesis enhances the understanding of physical interactions responsible for the preferred self-assembled macro-aggregates of surfactants and π-conjugated peptide derivatives. Integrated information from simulations and experiments provide insights to identify the controlling parameters to model and design the supra-structures with desirable functionalities relevant to the fields of industries or biotechnology.Item Slow Relaxations of Hydration Water near a Lipid Membrane: a Molecular Dynamics Study.(Indian Institute of Technology Jodhpur, 2020-09) Debnath, AnanyaWater is the most abundant molecule in cell membranes [1]. Water near membranes affects several biological processes such as transport of drugs and small molecules across the cell, influences formation of membrane rafts [2], molecular recognition and signal transduction [3]. In the past decade, with a major advancement of computer simulations and experimental techniques, water near bio and soft interfaces are found to have distinct properties with slow relaxations compared to that of the bulk water and these water molecules are termed as biological water [4-6]. However, molecular details of biological water from membrane experiments remain fragmentary due to the fluidity of membranes at physiological temperature and atomistic trajectories are still inaccessible. Moreover, the influence of water on global dynamics of membrane or protein are still debated [7-8]. Thus, the current work proceeds to investigate hydration water dynamics near lipid membranes using all atom molecular dynamics simulations to answer few pertinent questions.Capturing structure and dynamics of both lipids and water near membranes using computer simulations as in experiments is a challenging task till date. Thus, we aim to find most relevant water model and lipid force-field to understand dynamics of membrane and hydration layers using all atom molecular dynamics simulations. Dimyristoylphophatidylcholine (DMPC) lipid bilayers have been investigated at fluid phase where water residing continuously within ±3 Ǻ away from the interface are identified as interfacial water (IW). Our investigations show that TIP4P/2005 water model in combination with Berger lipid force field is most suitable to study hydration dynamics near a fluid lipid membrane [9]. IW hydrogen bonded solely among themselves and to carbonyl, phosphate and glycerol head groups of lipids are identified as IW-IW, IW-CO, IW-PO and IW-Glyc respectively. The mean square displacements and the re-orientational autocorrelation functions are slowest for the IW-CO since these are buried deep in the hydrophobic core among all interfacial water. The intermittent hydrogen bond auto-correlation functions of IW show eventual power law behavior of t-3/2 indicating translational diffusion dictated dynamics during hydrogen bond reaking and formation irrespective of the nature of chemical confinement. The analysis suggests that the networks in the hydration layer of membranes dynamically facilitate the water mediated lipid-lipid associations [10]. To find out the physical sources of universal slow relaxations of hydration layers and length-scale of the spatially heterogeneous dynamics, well established formalisms of glass dynamics have been mployed on the IW and the membrane. Two time-scales for the ballistic motions and hopping transitions are obtained from the self intermediate scattering functions of the IW molecules with an additional long relaxation which disappears for bulk water. Employing block analysis approach, the length-scale of dynamical heterogeneities of IW is captured which is comparable to the wavelength of the weak undulations of the membrane. The analysis provides a measure towards spatio-temporal scale of dynamical heterogeneity of confined water near membranes [11]. To gain access in membrane dynamics and its functionality towards various ological processes, investigations are carried out on coupling between hydration layer and bilayer dynamics. The IW molecules exhibit Fickian but intermittent dynamics due to vibrations in the local cage followed by translational jumps with eventual diffusion. Each IW molecule hydrogen bonded to a lipid head vibrates in a cage followed by a translational jump to another cage where it is again hydrogen bonded to another lipid head. The distribution of the logarithm of displacements of the IW shows a bimodal nature which is a characteristic of intermittent behavior leading to dynamical heterogeneity. The differences in regional dynamics of lipid heads are clearly reflected in the spatially resolved IW dynamics gradually from the deeper hydrophobic side to the outermost interface [12].In summary, the work provides insights on the hoice of force fields to apprehend physical laws of water relaxations near membranes. Role of water in membrane associations enables to gain deeper insights on thermodynamic stability of soft interfaces. The current study opens up a possible correlation between heterogeneous length scale and membrane curvature for rippled membranes in future. Our results indicate that hydration water dynamics can act as a sensitive flector of membrane phase and regional membrane dynamics. These will be useful to understand membrane functions such as molecular recognition, binding and domain formation and can contribute to control drug delivery and mimic cryo-preservation techniques for biomedical applications.